EP4108659A1 - Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs shp2 - Google Patents

Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs shp2 Download PDF

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EP4108659A1
EP4108659A1 EP21212393.9A EP21212393A EP4108659A1 EP 4108659 A1 EP4108659 A1 EP 4108659A1 EP 21212393 A EP21212393 A EP 21212393A EP 4108659 A1 EP4108659 A1 EP 4108659A1
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Prior art keywords
membered
alkyl
substituted
unsubstituted
alkoxy
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German (de)
English (en)
Inventor
Cunbo Ma
Panliang GAO
Jie CHU
Xinping WU
Chunwei WEN
Di KANG
Jinlong Bai
Xiaoyan PEI
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Jacobio Pharmaceuticals Co Ltd
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Jacobio Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to certain novel pyrazine derivatives (Formula I) as SHP2 inhibitors which is shown as formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic derivatives useful as inhibitors of SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder.
  • SHP2 The Src Homolgy-2 phosphatease
  • SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that harbors a classical tyrosine phosphatase domain and two N-terminal Src homology 2 (SH2) domains and a C-terminal tail.
  • SH2 N-terminal Src homology 2
  • the two SH2 domains control the subcellular localization and functional regulation of SHP2.
  • the N-terminal SH2 domain blocks the PTP domain and this autoinhibition is relieved by binding of the SH2 domains to specific phosphotyrosine sites on receptors or receptor-associated adaptor proteins.
  • the stimulation for example, by cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.
  • SHP2 is widely expressed and participated in multiple cell signaling processes, such as the Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, and insulin receptors and NF-kB pathways, in which plays an important role in proliferation, differentiation, cell cycle maintenance and migration.
  • the hyperactivation of SHP2 catalytic activity caused by either germline or somatic mutations in PTPN11 has been identified in patients with Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, myelodysplastic syndrome, B cell acute lymphoblastic leukemia/lymphoma, and acute myeloid leukemia.
  • activating mutations of PTPN11 have been found in solid tumors as well, such as lung cancer, colon cancer, melanoma, neuroblastoma, and hepatocellular carcinoma. Therefore, the presence of the activated or up-regulated SHP2 protein in human cancers and other disease make SHP2 an excellent target for development of novel therapies.
  • the compounds of the present invention fulfill the need of small molecules in order to inhibit the activity of SHP2.
  • the present invention relates to heterocyclic pyrazine compounds useful as SHP2 inhibitors and for the treatment of conditions mediated by SHP2.
  • the compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt:
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (I).
  • R 1 is -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , substituted or unsubstituted C 1-3 alkoxy, or substituted or unsubstituted C 1-3 alkyl.
  • R 1 is -H, -F, -Cl, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and each methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy is independently optionally substituted with halogen, OH or NH 2 .
  • R 2 is -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , substituted or unsubstituted C 1-3 alkoxy, or substituted or unsubstituted C 1-3 alkyl.
  • R 2 is -H, -F, -Cl, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and each methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy is independently optionally substituted with halogen, OH or NH 2 .
  • each G is independently 6-membered aryl, 7-membered aryl, 8-membered aryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic or 7-membered carbocyclic; and each of which may be optionally substituted with halogen, -CN, -OH, -NH 2 , -N 3 , -NO 2 , substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy.
  • each G is independently 6-membered aryl, 7-membered aryl, 8-membered aryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which may be optionally substituted with -F, -Cl, -Br, -CN, -OH, -NH 2 , -NO 2 , substituted or unsubstituted C 1-3 alkyl, or substituted or unsubstituted C 1-3 alkoxy.
  • each G is independently phenyl, and which may be optionally substituted with -F, -Cl, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and each methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy is independently optionally substituted with -F, -Cl, -Br or -I.
  • each G is independently 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl or 8-membered heteroaryl; and each of which contains 1, 2, 3 or 4 heteroatoms select from N, O or S, and may be optionally substituted with halogen, -CN, -OH, -NH 2 , -N 3 , -NO 2 , substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy.
  • p is 0 or 1.
  • q is 1 or 2.
  • R 3 is -NH 2 ,
  • R 4 is -Cl, -NH 2 , methyl or piperidinyl, wherein the ring system is optionally substituted with methyl, -NH 2 or -CH 2 NH 2 .
  • the C 6-9 heteroaryl contains 1, 2, 3 or 4 heteroatoms select from N, O or S, and the C 6-9 heteroaryl is 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl or 9-membered heteroaryl;
  • the C 6-17 heterocyclic contains 1, 2, 3, 4, 5, or 6 heteroatoms select from N, O, or S, and the C 6-17 heterocyclic is 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, 10-membered heterocyclic, 11-membered heterocyclic, 12-membered heterocyclic, 13-membered heterocyclic, 14-membered heterocyclic, 15-membered heterocyclic, 16-membered heterocyclic or 17-membered heterocyclic.
  • R 5 is -F, -Cl, -Br, -NR 8 R 9 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl, 6-membered arylalkyl, 7-membered arylalkyl, 8-membered arylalkyl, 9-membered arylalkyl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic 10-membered heterocyclic, 11-membered heterocyclic, 12-membered heterocyclic, 13-membered heterocyclic,
  • R 5 is
  • X is O, S or absent.
  • Y 1 is N and Y 2 is CR 2 .
  • Y 2 is N and Y 1 is CR 1 .
  • R 4 is -NH 2 .
  • R 5 is -NH 2 ,
  • each R 8 and R 9 is independently -H, halogen, CN, -OH, -NO 2 , -NH 2 , -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NH-C 1-6 alkyl, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -NHBoc, -CH 2 NHBoc; -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH-C 1-6 alkoxy, -N(C 1-6 alkoxy) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkylnyl, C 5-10 heterocyclic or C 5-10 carbocyclic; each of which may be optionally substituted.
  • each R 8 and R 9 is independently -H, -F, -Cl, -CN, -OH, -NO 2 , -NH 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc; -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 1-3 alkoxy, -N(C 1-3 alkoxy) 2 , C 1-4 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkylnyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, 10-membered heterocyclic, 5-membered carbo
  • the compound is of Formula II:
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (II).
  • ring is 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic; and each the ring systems contains 1, 2 or 3 heteroatoms select form N, O or S.
  • ring is 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms select form N or O, 6-membered heterocyclic ring containing 1 or 2 heteroatoms select form N or O or 5-membered carbocyclic.
  • each R 32 and R 33 is independently -CH 2 NH 2 , -CH 2 NHBoc or methyl.
  • Y 1 is N.
  • Y 2 is C.
  • Formula (II) is -H or -Cl.
  • R 4 is -NH 2 .
  • the compound is of Formula III:
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (III).
  • ring is 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring or 7-membered heterocyclic ring; and each of the ring system independently contains 1, 2 or 3 heteroatoms select form N, O or S.
  • ring is 5-membered heterocyclic ring or 6-membered heterocyclic ring; and each of the ring system independently contains 1 or 2 heteroatoms select form N or O.
  • R 26 is -H or -Cl
  • R 4 is -NH 2 .
  • each C 1-6 alkyl is independently methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-buyl, n-pentyl, neopentyl, isopentyl, cyclopentyl, n-hexyl or cyclohexyl.
  • each C 1-3 alkyl is independently methyl, ethyl, propyl, isopropyl or cyclopropyl.
  • each C 1-3 alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy or cyclopropyloxy.
  • each C 2-3 alkylnyl is independently -C ⁇ CH, -CH 2 -C ⁇ CH, or -C ⁇ C-CH 3 .
  • each halogen is independently -F, -Cl, -Br or -I.
  • each heterocyclic group and each carbocyclic group includes single ring, spiral ring, bridge ring, fused ring and all various combinations of spiral ring, bridge ring, and/or fused ring.
  • the said single ring includes the said spiral ring includes ; and the said various combinations of spiral ring, bridge ring, and/or fused ring include
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient.
  • the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
  • the present invention additionally provided a use of the pharmaceutical composition of as described herein for the preparation of a medicament.
  • a medicament thus prepared can be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
  • the present invention additionally provided a use of at least one compound described herein to prepare of a medicament.
  • a medicament thus prepared can be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
  • At least one compound for use described herein which is for use in the treatment of cancer, the prevention of cancer metastasis or the treatment of cardiovascular disease, an immunological disorder or an ocular disorder.
  • the condition mediated by the activity of SHP2 is cancer.
  • the condition mediated by the activity of SHP2 is noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma,neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.
  • At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament.
  • At least one compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer At least one compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • a method of treating cancer selected from the group consisting of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma,neuroblastoma, anaplastic large-cell lymphoma and glioblastoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof
  • halogen means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • halogen groups include F, Cl and Br.
  • fluoroC 1-6 alkyl, fluoroC 2-6 alkenyl, fluoroC 2-6 alkynyl and fluoroC 1-6 alkoxy groups in particular fluoroC 1-3 alkyl, for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • fluoroC 1-3 alkyl for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n- hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 - or -CH(CH 3 )-
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH(-CH 2 -CH 3 )- or -CH 2 -CH(CH 3 )-).
  • Alkenyl and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes.
  • C 2-8 alkenyl and “C 2-8 alkynyl” means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
  • aryl refers to an unsubstituted or substituted mono- or polycyclic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • heterocyclic refers to unsubstituted and substituted mono- or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms).
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • Examplary " cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) it shall be interpreted as including those limitations given above for"alkyl”and"aryl.”
  • Designated numbers of carbon atoms e.g., C 1-6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts".
  • the pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term "administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 .
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula I, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in- oil liquid emulsion.
  • the compound represented by Formula I, or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 1mg to about 2g of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or 1000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • Oxalyl chloride was added dropwise to a solution of 2-(dimethylamino)-2-oxoacetic acid (0.26 g, 2.15 mmol) in DCM (10mL),and stirred at RT for 2 hours, the volatiles were removed under reduced pressure, the residue was dissloved in DCM (10mL) and added dropwise to a solution of the compound 1e (0.55g, 1.08mmol) in DCM (10mL), after completion of the reaction, the reaction mixture was quenched by addition of ice-water (20mL), washed with brine, dried over anhydrous Na 2 SO 4 , filtered and the volatiles were removed under reduced pressure and purified by column chromatography to afford the compound 1f (0.42g, 64%). MS: 610(M+H) + .
  • Chloral hydrate (50.02g) and Na 2 SO 4 (350.21g) were dissolved in water (700mL) in a 3 L beaker and warmed to 35°C.
  • Example SHP2 inhibition(%) Example SHP2 inhibition(%) 3@0.1 ⁇ M 60 7@0.1 ⁇ M 79 8@0.1 ⁇ M 76 10@0.1 ⁇ M 81 20@0.1 ⁇ M 57 29@0.1 ⁇ M 47 31 @0.1 ⁇ M 53 32 @0.1 ⁇ M 49 34 @0.1 ⁇ M 37 35 @0.1 ⁇ M 30 38 @0.1 ⁇ M 30 40 @0.1 ⁇ M 71 42@0.1 ⁇ M 58 43@0.1 ⁇ M 43 58 @0.1 ⁇ M 61 72@0.1 ⁇ M 31 74@0.1 ⁇ M 75 75@0.1 ⁇ M 35
  • IC 50 values were estimated using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate, SHP2 samples (diluted to 0.5 nM in reaction buffer) were incubated with dPEG8 peptide for 30 min in reaction buffer[60 mM 3,3-dimethyl glutarate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol (DTT) ] to active the PTP.
  • DMSO 0.5% (v/v)] or compounds (concentrations ranging from 0.3 nM to 1 ⁇ M) were added to the mixture and incubated for 30 min at room temperature.
  • KYSE-520 (1500 cells/well) were plated onto 96-well plates in 100 ⁇ L medium (RPMI-1640 containing 3% FBS for KYSE-520 cells, Gibco).
  • compounds of the invention at various concentrations were added 24 hours after cell plating.
  • 50 ⁇ L MTS/PMS reagents (Promega/Sigma) were added, and the absorbance value was determined according to the supplier's instruction (Promega).
  • the IC 50 results of the compounds of the invention were shown by table 3. Table 3 Example IC 50 (( ⁇ M) Example IC 50 (( ⁇ M) 1 15.94 7 2.17 8 26.38 11 12.04 13 20.57 74 3.38
  • the compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995 ). The compounds of Formula I are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 1 mg to about 200 mg total daily dose, preferably 1 mg to 150 mg total daily dose, more preferably 1 mg to 50 mg total daily dose. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed.
  • the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
EP21212393.9A 2016-06-07 2017-06-07 Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs shp2 Pending EP4108659A1 (fr)

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Families Citing this family (111)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11466017B2 (en) 2011-03-10 2022-10-11 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
JO3517B1 (ar) 2014-01-17 2020-07-05 Novartis Ag ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2
JP7044375B2 (ja) 2016-05-31 2022-03-30 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム Ｐｔｐｎ１１の複素環式阻害剤
SG10202110874TA (en) * 2016-06-07 2021-11-29 Jacobio Pharmaceuticals Co Ltd Novel heterocyclic derivatives useful as shp2 inhibitors
ES2810852T3 (es) * 2016-06-14 2021-03-09 Novartis Ag Compuestos y composiciones para inhibir la actividad de shp2
KR20230156174A (ko) 2016-07-12 2023-11-13 레볼루션 메디슨즈, 인크. 다른자리 입체성 shp2 억제제로서의 2,5-이치환 3-메틸 피라진 및 2,5,6-3치환 3-메틸 피라진
EP3515916B1 (fr) 2016-09-22 2023-06-07 Relay Therapeutics, Inc. Inhibiteurs de phosphatase shp2 et leurs procédés d'utilisation
TW201819386A (zh) 2016-10-24 2018-06-01 美商傳達治療有限公司 Shp2磷酸酶抑制劑及其使用方法
CN110446709B (zh) 2017-01-23 2023-09-12 锐新医药公司 作为变构shp2抑制剂的二环化合物
AU2018210196B2 (en) 2017-01-23 2022-06-02 Revolution Medicines, Inc. Pyridine compounds as allosteric SHP2 inhibitors
EA201992253A1 (ru) * 2017-03-23 2020-03-31 Джакобио Фармасьютикалс Ко., Лтд. Новые гетероциклические производные, применимые в качестве ингибиторов shp2
US11591336B2 (en) 2017-05-26 2023-02-28 D. E. Shaw Research, Llc Substituted pyrazolo[3,4-b]pyrazines as SHP2 phosphatase inhibitors
WO2019051084A1 (fr) 2017-09-07 2019-03-14 Revolution Medicines, Inc. Compositions d'inhibiteur de la shp2 et méthodes de traitement du cancer
EP3681879A1 (fr) 2017-09-11 2020-07-22 Krouzon Pharmaceuticals, Inc. Inhibiteurs allostériques octahydrocyclopenta[c]pyrrole de shp2
EP3687997A1 (fr) 2017-09-29 2020-08-05 Relay Therapeutics, Inc. Dérivés de pyrazolo[3,4-b]pyrazine utilisés en tant qu'inhibiteurs de la phosphatase shp2
RU2020115095A (ru) 2017-10-12 2021-11-12 Революшн Медсинз, Инк. Пиридиновые, пиразиновые и триазиновые соединения в качестве аллостерических ингибиторов shp2
RU2020123241A (ru) 2017-12-15 2022-01-17 Революшн Медсинз, Инк. Полициклические соединения в качестве аллостерических ингибиторов shp2
KR102614939B1 (ko) 2018-02-13 2023-12-19 블루레이 테라퓨틱스 (상하이) 컴퍼니 리미티드 피리미딘-융합고리 화합물 및 그의 제조방법과 용도
SG11202006778TA (en) 2018-03-02 2020-08-28 Otsuka Pharma Co Ltd Pharmaceutical compounds
WO2019182960A1 (fr) 2018-03-21 2019-09-26 Synblia Therapeutics, Inc. Inhibiteurs de shp2 et leurs utilisations
BR112020019385A2 (pt) * 2018-03-21 2021-03-30 Relay Therapeutics, Inc. Inibidores de shp2 fosfatase e métodos de uso dos mesmos
MX2020010719A (es) 2018-04-10 2020-11-06 Revolution Medicines Inc Composiciones de inhibidores de shp2, metodos para tratar el cancer y metodos para identificar a un sujeto con mutaciones en shp2.
SG11202010822SA (en) 2018-05-02 2020-11-27 Navire Pharma Inc Substituted heterocyclic inhibitors of ptpn11
CN110143949A (zh) * 2018-05-09 2019-08-20 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
PE20211050A1 (es) 2018-08-10 2021-06-04 Navire Pharma Inc Inhibidores de ptpn11
US11459340B2 (en) * 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
WO2020063760A1 (fr) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
WO2020065452A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Fabrication de composés et de compositions pour inhiber l'activité de shp2
CA3113379A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Procede de fabrication d'un compose pour inhiber l'activite de shp2
WO2020072656A1 (fr) 2018-10-03 2020-04-09 Gilead Sciences, Inc. Dérivés d'imidozopyrimidine
EP3863636A1 (fr) 2018-10-08 2021-08-18 Revolution Medicines, Inc. Compositions d'inhibiteurs de shp2 destinées à être utilisées dans le traitement du cancer
TW202028183A (zh) * 2018-10-10 2020-08-01 大陸商江蘇豪森藥業集團有限公司 含氮雜芳類衍生物調節劑、其製備方法和應用
KR102649419B1 (ko) 2018-10-17 2024-03-21 어레이 바이오파마 인크. 단백질 티로신 포스파타제 억제제
CN117143079A (zh) 2018-11-06 2023-12-01 上海奕拓医药科技有限责任公司 一种螺芳环化合物及其应用
WO2020108590A1 (fr) 2018-11-30 2020-06-04 上海拓界生物医药科技有限公司 Pyrimidine et dérivé hétérocycle pentagonal de nitrogène, leur procédé de préparation et applications médicales
EA202190630A1 (ru) 2018-12-05 2021-10-11 Мирати Терапьютикс, Инк. Способы комбинированной терапии
JP2022522777A (ja) 2019-03-01 2022-04-20 レボリューション メディシンズ インコーポレイテッド 二環式ヘテロアリール化合物及びその使用
US20230096028A1 (en) 2019-03-01 2023-03-30 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
CN111647000B (zh) 2019-03-04 2021-10-12 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
AU2020232026A1 (en) 2019-03-07 2021-09-02 Merck Patent Gmbh Carboxamide-pyrimidine derivatives as shp2 antagonists
CA3135555C (fr) 2019-04-02 2023-09-19 Array Biopharma Inc. Inhibiteurs de proteine tyrosine phosphatase
JP2022527013A (ja) 2019-04-08 2022-05-27 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｓｈｐ２拮抗薬としてのピリミジノン誘導体
TWI826690B (zh) 2019-05-23 2023-12-21 美商基利科學股份有限公司 經取代之烯吲哚酮化物及其用途
EP3990476A1 (fr) 2019-06-25 2022-05-04 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
BR112021024674A2 (pt) * 2019-06-28 2022-05-31 Tuojie Biotech Shanghai Co Ltd Derivado heterocíclico de nitrogênio com cinco membros de pirimidina, método de preparação do mesmo e uso farmacêutico do mesmo
CN111704611B (zh) * 2019-07-25 2022-01-14 上海凌达生物医药有限公司 一类芳基螺环类shp2抑制剂化合物、制备方法和用途
EP3772513A1 (fr) 2019-08-09 2021-02-10 C.N.C.C.S. S.c.a.r.l. Collezione Nazionale Dei Composti Chimici e Centro Screening Inhibiteurs d'shp2
GB201911928D0 (en) * 2019-08-20 2019-10-02 Otsuka Pharma Co Ltd Pharmaceutical compounds
CN114127053B (zh) * 2019-09-06 2023-06-13 四川科伦博泰生物医药股份有限公司 一种取代吡嗪化合物、其制备方法和用途
JP2022548792A (ja) 2019-09-24 2022-11-21 リレー セラピューティクス， インコーポレイテッド Ｓｈｐ２ホスファターゼ阻害剤並びにその作製方法及び使用方法
CN112724145A (zh) * 2019-10-14 2021-04-30 杭州雷索药业有限公司 用于抑制shp2活性的吡嗪衍生物
EP4045083B1 (fr) 2019-10-18 2024-01-10 Forty Seven, Inc. Polythérapies pour le traitement de syndromes myélodysplasiques et de la leucémie myéloïde aiguë
CA3153636A1 (fr) 2019-10-31 2021-05-06 Forty Seven, Inc. Traitement d'un cancer du sang base sur une therapie anti-cd47 et anti-cd20
TW202132314A (zh) 2019-11-04 2021-09-01 美商銳新醫藥公司 Ｒａｓ抑制劑
EP4054719A1 (fr) 2019-11-04 2022-09-14 Revolution Medicines, Inc. Inhibiteurs de ras
CA3159559A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
PE20230249A1 (es) 2019-11-08 2023-02-07 Revolution Medicines Inc Compuestos de heteroarilo biciclicos y usos de estos
TWI778443B (zh) 2019-11-12 2022-09-21 美商基利科學股份有限公司 Mcl1抑制劑
JP2023505100A (ja) 2019-11-27 2023-02-08 レボリューション メディシンズ インコーポレイテッド 共有ｒａｓ阻害剤及びその使用
PE20230376A1 (es) 2019-12-24 2023-03-06 Carna Biosciences Inc Compuestos moduladores de la diacilglicerol quinasa
BR112022010086A2 (pt) 2020-01-07 2022-09-06 Revolution Medicines Inc Dosagem do inibidor de shp2 e métodos de tratamento de câncer
CN113135910A (zh) * 2020-01-19 2021-07-20 北京诺诚健华医药科技有限公司 嘧啶-4(3h)-酮类杂环化合物、其制备方法及其在医药学上的应用
US11692038B2 (en) 2020-02-14 2023-07-04 Gilead Sciences, Inc. Antibodies that bind chemokine (C-C motif) receptor 8 (CCR8)
WO2021171261A1 (fr) 2020-02-28 2021-09-02 Novartis Ag Combinaison pharmaceutique triple comprenant du dabrafénib, un inhibiteur d'erk et un inhibiteur de shp2
CN115362149A (zh) * 2020-04-26 2022-11-18 贝达药业股份有限公司 Shp2抑制剂及其组合物和应用
CN115279749A (zh) * 2020-04-30 2022-11-01 贝达药业股份有限公司 Shp2抑制剂及其组合物和应用
US20240043427A1 (en) 2020-05-01 2024-02-08 Gilead Sciences, Inc. Cd73 compounds
CN113754683A (zh) 2020-06-05 2021-12-07 上海奕拓医药科技有限责任公司 同位素取代的螺芳环化合物及其应用
CN115916194A (zh) 2020-06-18 2023-04-04 锐新医药公司 用于延迟、预防和治疗针对ras抑制剂的获得性抗性的方法
AU2021344830A1 (en) 2020-09-03 2023-04-06 Revolution Medicines, Inc. Use of SOS1 inhibitors to treat malignancies with SHP2 mutations
KR20230067635A (ko) 2020-09-15 2023-05-16 레볼루션 메디슨즈, 인크. 암의 치료에서 ras 억제제로서 인돌 유도체
CN117396472A (zh) 2020-12-22 2024-01-12 上海齐鲁锐格医药研发有限公司 Sos1抑制剂及其用途
EP4039685A1 (fr) 2021-02-08 2022-08-10 Irbm S.P.A. Inhibiteurs azabicycliques de shp2
US20240025924A1 (en) * 2021-03-23 2024-01-25 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Heterocycle substituted ketone derivative, and composition and medicinal use thereof
EP4067358A1 (fr) 2021-04-02 2022-10-05 C.N.C.C.S. S.c.a.r.l. Collezione Nazionale Dei Composti Chimici e Centro Screening Dérivés de (s)-1-(5-((pyridin-3-yl)thio)pyrazin-2-yl)-4'h,6'h-spiro[pipéridine-4,5'-pyrrolo[1,2-b]pyrazol]-4'-amine et composés similaires en tant qu'inhibiteurs de shp2 pour le traitement par ex. du cancer
TW202302145A (zh) 2021-04-14 2023-01-16 美商基利科學股份有限公司 ＣＤ４７／ＳＩＲＰα結合及ＮＥＤＤ８活化酶Ｅ１調節次單元之共抑制以用於治療癌症
CR20230570A (es) 2021-05-05 2024-01-22 Revolution Medicines Inc Inhibidores de ras
CN117500811A (zh) 2021-05-05 2024-02-02 锐新医药公司 共价ras抑制剂及其用途
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
CN114716448B (zh) * 2021-05-13 2024-01-30 中国科学院上海药物研究所 抑制shp2活性的杂环化合物、其制备方法及用途
TW202313094A (zh) 2021-05-18 2023-04-01 美商基利科學股份有限公司 使用ＦＬＴ３Ｌ—Ｆｃ融合蛋白之方法
TW202313041A (zh) 2021-06-09 2023-04-01 瑞士商諾華公司 包含達拉菲尼、曲美替尼和shp2抑制劑之三重藥物組合
US11932634B2 (en) 2021-06-23 2024-03-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
TW202317100A (zh) 2021-06-23 2023-05-01 瑞士商諾華公司 包含ｋｒａｓ ｇ１２ｃ抑制劑的藥物組合及其用於治療癌症之用途
CN117377671A (zh) 2021-06-23 2024-01-09 吉利德科学公司 二酰基甘油激酶调节化合物
KR20240005901A (ko) 2021-06-23 2024-01-12 길리애드 사이언시즈, 인코포레이티드 디아실글리세롤 키나제 조절 화합물
EP4359415A1 (fr) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
AU2022309195A1 (en) * 2021-07-09 2024-01-25 Kanaph Therapeutics Inc. Shp2 inhibitor and use thereof
CN113461538A (zh) * 2021-07-12 2021-10-01 无锡双启科技有限公司 一种2-氯-3-溴苯胺的制备方法
CA3224341A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
AR127308A1 (es) 2021-10-08 2024-01-10 Revolution Medicines Inc Inhibidores ras
TW202330504A (zh) 2021-10-28 2023-08-01 美商基利科學股份有限公司 嗒𠯤—３（２ｈ）—酮衍生物
US11919869B2 (en) 2021-10-29 2024-03-05 Gilead Sciences, Inc. CD73 compounds
US20230220106A1 (en) 2021-12-08 2023-07-13 Dragonfly Therapeutics, Inc. Antibodies targeting 5t4 and uses thereof
US20230203202A1 (en) 2021-12-08 2023-06-29 Dragonfly Therapeutics, Inc. Proteins binding nkg2d, cd16 and 5t4
US20240124412A1 (en) 2021-12-22 2024-04-18 Gilead Sciences, Inc. Ikaros zinc finger family degraders and uses thereof
WO2023122615A1 (fr) 2021-12-22 2023-06-29 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
WO2023122938A1 (fr) * 2021-12-28 2023-07-06 Js Innomed Holdings Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de shp2, compositions comprenant le composé hétérocyclique, et leurs procédés d'utilisation
TW202340168A (zh) 2022-01-28 2023-10-16 美商基利科學股份有限公司 Ｐａｒｐ７抑制劑
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023169170A1 (fr) * 2022-03-10 2023-09-14 捷思英达控股有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de shp2, composition comprenant un composé hétérocyclique, et procédé l'utilisant
WO2023178181A1 (fr) 2022-03-17 2023-09-21 Gilead Sciences, Inc. Agents de dégradation des doigts de zinc de la famille ikaros et leurs utilisations
US20230355796A1 (en) 2022-03-24 2023-11-09 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
TW202345901A (zh) 2022-04-05 2023-12-01 美商基利科學股份有限公司 用於治療結腸直腸癌之組合療法
TW202400138A (zh) 2022-04-21 2024-01-01 美商基利科學股份有限公司 Ｋｒａｓ ｇ１２ｄ調節化合物
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
US20240091351A1 (en) 2022-09-21 2024-03-21 Gilead Sciences, Inc. FOCAL IONIZING RADIATION AND CD47/SIRPa DISRUPTION ANTICANCER COMBINATION THERAPY
EP4345101A1 (fr) 2022-09-29 2024-04-03 Irbm S.P.A. Dérivés d'azole utilisés en tant qu'inhibiteurs de shp2

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107495A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Composés n-hétéroaryle substitués par un n-azaspirocycloalcane et compositions pour inhiber l'activité de shp2
WO2015107493A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine et compositions les contenant pour l'inhibition de l'activité de shp2
WO2015107494A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine et compositions les contenant pour l'inhibition de l'activité de shp2
WO2016203406A1 (fr) * 2015-06-19 2016-12-22 Novartis Ag Composés et compositions pour inhiber l'activité de shp2
WO2017216706A1 (fr) * 2016-06-14 2017-12-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité de shp2
WO2018130928A1 (fr) * 2017-01-10 2018-07-19 Novartis Ag Combinaison pharmaceutique comprenant un inhibiteur d'alk et un inhibiteur de shp2
WO2018140286A1 (fr) * 2017-01-25 2018-08-02 Indiana University Research And Technology Corporation Prophylaxie et traitement de la leucémie myéloïde aiguë
WO2018172984A1 (fr) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2

Family Cites Families (166)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3377826B2 (ja) 1993-05-06 2003-02-17 ヘキスト・アクチェンゲゼルシャフト 液晶組成物に使用するための新規化合物
DE69634045T2 (de) 1995-10-31 2005-05-19 Eli Lilly And Co., Indianapolis Antithrombotische diamine
EP1154997A4 (fr) 1999-01-26 2002-11-04 Dana Farber Cancer Inst Inc Composes pharmaceutiquement actifs et procedes d'utilisation
US7375125B2 (en) 1999-08-04 2008-05-20 Ore Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
ES2318649T3 (es) 2000-10-20 2009-05-01 EISAI R&D MANAGEMENT CO., LTD. Procedimiento de preparacion de derivados de 4-fenoxi quinolinas.
US20050019424A1 (en) 2001-12-21 2005-01-27 Adams Paul E. Anti-angiogenesis combination therapies comprising pyridazine or pyridine derivatives
JP4467307B2 (ja) 2002-02-22 2010-05-26 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー ５−ｈｔ受容体アンタゴニストとしてのピリジルスルホン誘導体
DE10246657A1 (de) 2002-10-07 2004-04-15 Merck Patent Gmbh Chirales Phenolderivat, dieses enthaltendes Flüssigkristallmedium, Verfahren zur Herstellung eines Flüssigkristallmediums und elektrooptische Flüssigkristallanzeige
CN101077867B (zh) 2002-11-18 2012-10-10 坎莫森特里克斯公司 芳基磺酰胺
SE0203712D0 (sv) 2002-12-13 2002-12-13 Astrazeneca Ab Novel compounds
MXPA05008368A (es) 2003-02-07 2005-11-04 Janssen Pharmaceutica Nv 1,2,4-triazinas inhibidoras del virus de inmunodeficiencia humana.
CA2515544A1 (fr) 2003-02-11 2004-08-26 Kemia Inc. Composes destines au traitement d'une infection virale
GB2400101A (en) 2003-03-28 2004-10-06 Biofocus Discovery Ltd Compounds capable of binding to the active site of protein kinases
US20040242886A1 (en) 2003-04-30 2004-12-02 Sandeep Gupta Monocyclic diazodioxide based Bcl-2 protein antagonists related applications
US7393873B2 (en) 2003-07-02 2008-07-01 Merck & Co., Inc. Arylsulfonamide derivatives
EP1654264A1 (fr) 2003-07-08 2006-05-10 AstraZeneca AB Derives de spiro [1-azabicyclo [2.2.2]octan-3,5 '-oxazolidin -2' -one] possedant une affinite avec le recepteur d´ acetylcholine nicotinique alpha7
US7390907B2 (en) 2003-09-30 2008-06-24 Amgen Inc. Vanilloid receptor ligands and their use in treatments
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
TW200528459A (en) 2004-01-06 2005-09-01 Achillion Pharmaceuticals Inc Azabenzofuran substituted thioureas; inhibitors of viral replication
CA2545427C (fr) 2004-01-12 2012-08-21 Cytopia Research Pty Ltd Inhibiteurs selectifs de kinases
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
EP1720545B1 (fr) 2004-03-03 2014-10-29 ChemoCentryx, Inc. Heterocycles d'azote bicycliques et ponts
US7687502B2 (en) * 2004-03-23 2010-03-30 Banyu Pharmaceutical Co., Ltd. Substituted quinazoline or pyridopyrimidine derivative
JP4865702B2 (ja) 2004-05-03 2012-02-01 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド サイトカイン阻害剤
NZ551603A (en) 2004-06-24 2010-11-26 Incyte Corp N-substituted piperidines and their use as pharmaceuticals
US20070043057A1 (en) 2005-02-09 2007-02-22 Threshold Pharmaceuticals, Inc. Lonidamine analogs
BRPI0517272A (pt) 2004-10-29 2008-10-07 Tibotec Pharm Ltd derivados de pirimidina bicìclicos de inibição de hiv
WO2006063010A2 (fr) 2004-12-08 2006-06-15 Nuada, Llc Composes et procedes d'utilisation
GB0428082D0 (en) 2004-12-22 2005-01-26 Welcome Trust The Ltd Therapeutic compounds
CA2592021A1 (fr) 2004-12-23 2006-07-06 Raghavan Rajagopalan Derives de pyrazine fluorescents et methodes d'utilisation de ces derives a des fins d'evaluation de la fonction renale
US7622583B2 (en) 2005-01-14 2009-11-24 Chemocentryx, Inc. Heteroaryl sulfonamides and CCR2
JP4734346B2 (ja) 2005-02-04 2011-07-27 セノミックス インコーポレイテッド 連結ヘテロアリール部分を含む化合物、ならびに食用組成物のための新規なうまみフレーバー改変剤、味物質および味覚増強剤としての使用
EP1866314B1 (fr) 2005-02-16 2010-09-15 NeuroSearch A/S Derives aryle diazabicycliques et utilisation medicale
WO2007046867A2 (fr) 2005-05-19 2007-04-26 Xenon Pharmaceuticals Inc. Derives de piperidine et leurs utilisations comme agents therapeutiques
BRPI0610580B8 (pt) 2005-05-30 2021-05-25 Banyu Pharma Co Ltd composto derivado de piperidina
JP2007013804A (ja) 2005-07-01 2007-01-18 Mitsubishi Electric Corp 属性指定通信方法および通信装置
EP1909797A4 (fr) * 2005-08-02 2013-02-27 Neurogen Corp Dipipérazinyl cétones et analogues apparentés
NZ593684A (en) 2005-10-19 2012-11-30 Gruenenthal Chemie Novel vanilloid receptor ligands and their use for producing medicaments
WO2007057742A2 (fr) 2005-11-18 2007-05-24 Pfizer Products Inc. Nouveaux derives de piperazinone
JPWO2007063868A1 (ja) 2005-11-29 2009-05-07 東レ株式会社 アリールメチレンウレア誘導体及びその用途
CN101346368A (zh) 2005-12-21 2009-01-14 詹森药业有限公司 作为α2C－肾上腺素受体拮抗剂的取代的吡嗪酮衍生物
CN101405000A (zh) 2006-01-19 2009-04-08 艾博特公司 2-亚胺基-苯并咪唑化合物
WO2007089857A2 (fr) 2006-01-30 2007-08-09 Transtech Pharma, Inc. Derives d'imidazole a substitution, compositions et procedes d'utilisation en tant qu'inhibiteurs de ptpase
AU2007224020A1 (en) 2006-03-07 2007-09-13 Array Biopharma Inc. Heterobicyclic pyrazole compounds and methods of use
US20090111801A1 (en) 2006-04-20 2009-04-30 Janssen Pharmaceutica N.V. Substituted pyrazinone derivatives for use as a medicine
WO2007135131A1 (fr) 2006-05-22 2007-11-29 Janssen Pharmaceutica N.V. Dérivés de pyrazinone substitués à utiliser comme médicament
US7838523B2 (en) 2006-09-11 2010-11-23 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
AR063707A1 (es) 2006-09-11 2009-02-11 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmacéuticas que las comprenden.
BRPI0717822A2 (pt) 2006-10-04 2013-11-12 Hoffmann La Roche Composto, processo de fabricação de composto da fórmula i, composição farmacêutica, método de tratamento e/ou profilaxia de doenças que são associadas à modulação de receptores de cb2 e uso de composto.
DE102007018150A1 (de) 2007-04-16 2008-10-23 Grünenthal GmbH VR1-Rezeptor-Liganden und µ-Opioid-Rezeptor-Liganden zur Behandlung von Schmerz
JP2010518083A (ja) 2007-02-12 2010-05-27 メルク・シャープ・エンド・ドーム・コーポレイション ピペリジン誘導体
EP2137158A4 (fr) 2007-02-28 2012-04-18 Methylgene Inc Inhibiteurs à petite molécule de protéines arginine méthyltransférases (prmt)
EP2131861A2 (fr) 2007-03-01 2009-12-16 Mallinckrodt Inc. Petites molécules photoactives intégrées et leurs utilisations
BRPI0808523A2 (pt) 2007-03-01 2014-08-19 Novartis Vaccines & Diagnostic Inibidores de pim cinase e métodos de seu uso
WO2008112674A1 (fr) 2007-03-12 2008-09-18 Irm Llc Composés et compositions comme inhibiteurs de l'activité du récepteur cannabinoïde 1
WO2009033084A1 (fr) 2007-09-06 2009-03-12 Array Biopharma Inc. Pyrazolo-pyridines en tant qu'inhibiteurs de tyrosine kinase
WO2009036066A1 (fr) 2007-09-10 2009-03-19 Curis, Inc. Inhibiteurs du récepteur du facteur de croissance endothélial vasculaire (vegfr) contenant une fraction de liaison au zinc
EP2197873B1 (fr) 2007-09-20 2014-07-16 Irm Llc Composés et compositions en tant que modulateurs de l'activité de gpr119
BRPI0817835A2 (pt) 2007-10-18 2015-03-31 Boehringer Ingelheim Int Antagonistas cgrp
US20100216816A1 (en) 2007-10-24 2010-08-26 Barrow James C Pyrazinyl amide-t type calcium channel antagonists
JP2011513323A (ja) 2008-02-29 2011-04-28 シェーリング コーポレイション アルツハイマー病の治療のためのγ−セクレターゼモジュレーター
EP2278973B1 (fr) 2008-04-07 2011-11-02 Amgen Inc. Amino-pyridines/pyrimidines spirocycliques et gem-disubstituées en tant qu'inhibiteurs du cycle cellulaire
CL2009001064A1 (es) 2008-05-07 2009-10-09 Galapagos Nv Compuestos derivados de imidazol-pirazina o triazol-pirazina fusionados, inhibidores de mapkapk5; composicion farmaceutica que comprende dichos compuestos; y uso para preparar un medicamento destinado al tratamiento de inflamacion, especialmente en la artritis reumatoide.
EP2328586A2 (fr) 2008-05-20 2011-06-08 Cephalon, Inc. Dérivés pyridazinone substitués comme ligands des récepteurs de l'histamine-3 (h3)
MX2010013876A (es) 2008-06-20 2011-03-04 Metabolex Inc Agonistas de arilo grpr119 y sus usos .
WO2010020675A1 (fr) 2008-08-22 2010-02-25 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
CA2738429C (fr) 2008-09-26 2016-10-25 Intellikine, Inc. Inhibiteurs heterocycliques de kinases
ES2397934T3 (es) 2008-12-17 2013-03-12 Amgen Inc. Compuestos de aminopiridina y carboxipiridina como inhibidores de fosfodiesterasa 10
WO2010070022A1 (fr) 2008-12-19 2010-06-24 Boehringer Ingelheim International Gmbh Nouveaux composés
KR20110098749A (ko) 2008-12-25 2011-09-01 다이쇼 세이야꾸 가부시끼가이샤 이소퀴놀린 유도체
KR20110119707A (ko) 2009-01-22 2011-11-02 유니진 래보러토리즈 인코포레이티드 비만 치료
WO2010086613A1 (fr) 2009-01-30 2010-08-05 Betagenon Ab Composés utiles en tant qu'inhibiteurs tel que ampk
CN102438624B (zh) 2009-03-13 2016-03-30 阿德维纳斯治疗私人有限公司 取代的稠合嘧啶化合物
SG177558A1 (en) 2009-07-08 2012-02-28 Baltic Bio Ab 1, 2, 4-thiazolidin-3-one derivatives and their use in the treatment of cancer
EP2467142B1 (fr) 2009-08-17 2016-09-21 Memorial Sloan-Kettering Cancer Center Dérivés 2-(pyrimidin-5-yl)-thiopyrimidine en tant que modulateurs Hsp70 and Hsc70 pour le traitement de maladies proliferatives
WO2011027249A2 (fr) 2009-09-01 2011-03-10 Pfizer Inc. Dérivés de benzimidazole
US8575168B2 (en) 2009-10-09 2013-11-05 Irm Llc Compounds and compositions as modulators of GPR119 activity
US8759377B2 (en) 2009-11-23 2014-06-24 Vanderbilt University Substituted dioxopiperidines and dioxopyrrolidines as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
ES2438509T3 (es) 2009-12-14 2014-01-17 Merck Patent Gmbh Inhibidores de la esfingosina quinasa
WO2011075607A1 (fr) 2009-12-18 2011-06-23 Intermune, Inc. Nouveaux inhibiteurs de la réplication du virus de l'hépatite c
TWI510241B (zh) 2010-02-18 2015-12-01 Vtv Therapeutice Llc 苯基－雜芳基衍生物及其使用方法
JP5918214B2 (ja) 2010-04-13 2016-05-18 ノバルティス アーゲー がんを治療するためのサイクリン依存性キナーゼ４またはサイクリン依存性キナーゼ（ｃｄｋ４／６）阻害剤およびｍｔｏｒ阻害剤を含む組合せ
DK2563780T3 (en) 2010-04-29 2015-07-27 Univ Edinburgh 3,3-DISUBSTITUEREDE- (8-aza-bicyclo [3.2.1] oct-8-yl) - [5- (1H-pyrazol-4-yl) -thiophene-3-yl] -METHANONER as inhibitors of 11 ( BETA) -HSD1
US20110312996A1 (en) 2010-05-17 2011-12-22 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
AU2011258217B2 (en) 2010-05-26 2016-12-15 Sunovion Pharmaceuticals Inc. Heteroaryl compounds and methods of use thereof
NZ605692A (en) 2010-07-29 2015-04-24 Rigel Pharmaceuticals Inc Ampk-activating heterocyclic compounds and methods for using the same
JP2013230986A (ja) 2010-08-25 2013-11-14 Kyorin Pharmaceutical Co Ltd 新規ヒダントイン誘導体及びそれらを有効成分とする医薬
CN102432598A (zh) 2010-09-29 2012-05-02 江苏恒瑞医药股份有限公司 三环化合物、其制备方法及其在医药上的应用
US20140066431A1 (en) * 2010-11-15 2014-03-06 Exelixis, Inc. Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture
GB201020161D0 (en) 2010-11-26 2011-01-12 Almac Discovery Ltd Pharmaceutical compounds
CN103298460B (zh) 2010-12-14 2016-06-01 电泳有限公司 酪蛋白激酶1δ(CK1δ)抑制剂
US8987271B2 (en) 2010-12-22 2015-03-24 Eutropics Pharmaceuticals, Inc. 2,2′-biphenazine compounds and methods useful for treating disease
US20120184572A1 (en) 2011-01-13 2012-07-19 Metabolex, Inc. Aryl gpr119 agonists and uses thereof
US20140142094A1 (en) 2011-04-29 2014-05-22 Icahn School Of Medicine At Mount Sinai Kinase inhibitors
WO2012158784A2 (fr) 2011-05-16 2012-11-22 Theodore Mark Kamenecka Modulateurs des récepteurs orphelins apparentés aux récepteurs hormonaux nucléaires
WO2012170931A2 (fr) * 2011-06-10 2012-12-13 Calcimedica, Inc. Composés qui modulent le calcium intracellulaire
EP2554544A1 (fr) 2011-08-01 2013-02-06 Almirall, S.A. Dérivés de pyridin-2(1h)-one en tant qu'inhibiteurs de JAK
WO2013039851A1 (fr) 2011-09-12 2013-03-21 Mallinckrodt Llc Agents optiques permettant d'obtenir des images de métalloprotéases matricielles et de les visualiser
MX365923B (es) 2011-12-12 2019-06-20 Celgene Int Ii Sarl Derivados de acido carboxilico que comprenden cuatro ciclos, que actuan como moduladores del receptor del peptido 1 similar al glucagon (glp-1) para terapia de enfermedades como la diabetes.
WO2013124040A1 (fr) 2012-02-22 2013-08-29 Merck Patent Gmbh Milieu cristallin liquide
GB201204985D0 (en) 2012-03-21 2012-05-02 Genentech Inc Compounds
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
CA2870992C (fr) 2012-04-25 2020-07-14 Raqualia Pharma Inc. Derives d'amide comme bloqueurs de ttx-s
WO2013167633A1 (fr) 2012-05-09 2013-11-14 Basf Se Composés d'acrylamide pour la lutte contre des animaux nuisibles invertébrés
CA2871388A1 (fr) 2012-06-27 2014-01-03 F. Hoffmann-La Roche Ag Composes 5-azaindazole et methodes d'utilisation
WO2014000178A1 (fr) 2012-06-27 2014-01-03 Merck Sharp & Dohme Corp. Dérivés de sulfamide et leurs méthodes d'utilisation permettant d'améliorer la pharmacocinétique d'un médicament
US9682966B2 (en) 2012-08-16 2017-06-20 The Scripps Research Institute Kappa opioid ligands
MA37975B2 (fr) 2012-09-11 2021-03-31 Genzyme Corp Inhibiteurs de synthase de glucosylcéramide
AU2013341115B2 (en) * 2012-11-09 2016-07-14 Glaxosmithkline Llc Novel compounds as diacylglycerol acyltransferase inhibitors
CN105121404A (zh) 2013-03-15 2015-12-02 豪夫迈·罗氏有限公司 作为RORc调节剂的芳基磺酰胺和氨基磺酸衍生物
CN105407889B (zh) 2013-03-15 2018-06-01 G1治疗公司 针对Rb阳性异常细胞增殖的HSPC节制性治疗
WO2014184074A1 (fr) 2013-05-15 2014-11-20 Basf Se Composés de n-(tétrazol-5-yl)- et n-(triazol-5-yl)hétarylcarboxamide substitués et leur utilisation en tant qu'herbicides
WO2014184014A1 (fr) 2013-05-15 2014-11-20 Basf Se Composés de n-(1,2,5-oxadiazol-3-yl)carboxamide et leur utilisation en tant qu'herbicides
GB201309508D0 (en) 2013-05-28 2013-07-10 Redx Pharma Ltd Compounds
EA030857B1 (ru) 2013-06-11 2018-10-31 Селджин Интернэшнл Ii Сарл Новые модуляторы рецептора glp-1
EP3016652A4 (fr) 2013-07-03 2017-03-08 Indiana University Research and Technology Corporation Inhibiteurs de shp2 et méthodes de traitement de maladies auto-immunes et associées à la glomérulonéphrite à l'aide d'inhibiteurs de shp2
CN104341386A (zh) * 2013-07-23 2015-02-11 中国科学院上海药物研究所 一类芳基杂环小分子化合物、其衍生物及其制备方法和用途
EP3029031A4 (fr) 2013-07-30 2017-01-11 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US9751881B2 (en) 2013-07-31 2017-09-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US20150087673A1 (en) 2013-09-26 2015-03-26 Rigel Pharmaceuticals, Inc. Methods for using and biomarkers for ampk-activating compounds
KR102307387B1 (ko) 2013-10-08 2021-09-30 큉-빈 루 표적화된 화학요법에 사용하기 위한 비­백금­기반 항암 화합물
PT3060550T (pt) 2013-10-21 2019-08-27 Merck Patent Gmbh Compostos de heteroarilo como inibidores de btk e utilizações dos mesmos
KR20150070027A (ko) 2013-12-16 2015-06-24 메르크 파텐트 게엠베하 액정 매질
US9624199B2 (en) 2013-12-19 2017-04-18 Bayer Pharma Aktiengesellschaft Substituted bipiperidinyl derivatives
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
PE20170245A1 (es) 2014-02-14 2017-03-30 Takeda Pharmaceuticals Co Pirazinas moduladoras de gpr 6
WO2015148714A1 (fr) 2014-03-25 2015-10-01 Duke University Ligands de récepteurs de la protéine de choc thermique 70 (hsp-70)
US9856258B2 (en) 2014-04-07 2018-01-02 Netherlands Translational Research Center B.V. (5,6-dihydro)pyrimido[4,5-E]indolizines
CA2949229A1 (fr) 2014-05-23 2015-11-26 F. Hoffmann-La Roche Ag Derives de benzene sulfonamide et leur utilisation comme modulateurs de rorc
CN105294655B (zh) 2014-07-26 2019-03-15 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
WO2016022644A1 (fr) 2014-08-06 2016-02-11 Merck Sharp & Dohme Corp. Antagonistes hétérocycliques des récepteurs cgrp
WO2016022645A1 (fr) 2014-08-06 2016-02-11 Merck Sharp & Dohme Corp. Antagonistes hétérocycliques du récepteur du cgrp
EP2985334B1 (fr) 2014-08-15 2018-06-20 Merck Patent GmbH Milieu liquide cristallin
JP6692350B2 (ja) * 2014-09-05 2020-05-13 セルジーン クオンティセル リサーチ，インク． リジン特異的なデメチラーゼ−１の阻害剤
WO2016040449A1 (fr) 2014-09-10 2016-03-17 Raze Therapeutics, Inc. Inhibiteurs de la 3-phosphoglycérate déshydrogénase) et leurs utilisations
TWI788655B (zh) 2015-02-27 2023-01-01 美商林伯士拉克許米公司 酪胺酸蛋白質激酶2(tyk2)抑制劑及其用途
CN107428731B (zh) 2015-03-11 2020-05-05 正大天晴药业集团股份有限公司 作为抗癌药物的取代的2-氢-吡唑衍生物
EP3273959A1 (fr) 2015-03-25 2018-01-31 Novartis Ag Combinaisons pharmaceutiques
EP3302057A4 (fr) 2015-06-04 2018-11-21 Kura Oncology, Inc. Méthodes et compositions d'inhibition de l'interaction de la ménine avec les protéines mll
TWI703150B (zh) 2015-06-04 2020-09-01 美商庫拉腫瘤技術股份有限公司 用於抑制ｍｅｎｉｎ及ｍｌｌ蛋白之交互作用的方法及組合物
JP6878316B2 (ja) * 2015-06-19 2021-05-26 ノバルティス アーゲー Ｓｈｐ２の活性を阻害するための化合物および組成物
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
RU2604047C1 (ru) 2015-07-10 2016-12-10 Фортис Аксис, Закрытое Акционерное Общество Массажёр для воздействия на мышцы спины трех отделов позвоночника
AU2016324598A1 (en) 2015-09-17 2018-03-15 Marvin J. Miller Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection
CN113549069A (zh) 2015-12-27 2021-10-26 重庆复创医药研究有限公司 一类激酶抑制剂
WO2017156397A1 (fr) 2016-03-11 2017-09-14 Board Of Regents, The University Of Texas Sysytem Inhibiteurs hétérocycliques de ptpn11
TWI772291B (zh) 2016-03-25 2022-08-01 大陸商正大天晴藥業集團股份有限公司 取代的吡咯並嘧啶類ｃｄｋ抑制劑、包含其藥物組合物及其用途
CN107286150B (zh) 2016-04-11 2020-07-07 中国科学院上海有机化学研究所 N-杂环类化合物、其中间体、制备方法、药物组合物和应用
JP7044375B2 (ja) 2016-05-31 2022-03-30 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム Ｐｔｐｎ１１の複素環式阻害剤
SG10202110874TA (en) * 2016-06-07 2021-11-29 Jacobio Pharmaceuticals Co Ltd Novel heterocyclic derivatives useful as shp2 inhibitors
KR20230156174A (ko) 2016-07-12 2023-11-13 레볼루션 메디슨즈, 인크. 다른자리 입체성 shp2 억제제로서의 2,5-이치환 3-메틸 피라진 및 2,5,6-3치환 3-메틸 피라진
EP3290412A1 (fr) 2016-08-31 2018-03-07 Università degli Studi di Siena Inhibiteurs des nucléocapsides du vih-1
EP3515916B1 (fr) 2016-09-22 2023-06-07 Relay Therapeutics, Inc. Inhibiteurs de phosphatase shp2 et leurs procédés d'utilisation
WO2018089433A1 (fr) 2016-11-08 2018-05-17 Navitor Pharmaceuticals, Inc. Inhibiteurs de mtorc phényle et leurs utilisations
EP3565810A1 (fr) 2017-01-03 2019-11-13 ViiV Healthcare UK (No.5) Limited Dérivés d'acide pyridin-3-yle acétique utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
CN114213421A (zh) 2017-04-01 2022-03-22 晟科药业（江苏）有限公司 1h-咪唑[4,5-h]喹唑啉类化合物作为蛋白激酶抑制剂
KR20200027992A (ko) 2017-07-12 2020-03-13 반더빌트유니버시티 무스카린성 아세틸콜린 수용체 m4의 길항제
RU2020115095A (ru) 2017-10-12 2021-11-12 Революшн Медсинз, Инк. Пиридиновые, пиразиновые и триазиновые соединения в качестве аллостерических ингибиторов shp2
CA3079617A1 (fr) 2017-10-20 2019-04-25 Vanderbilt University Antagonistes du recepteur muscarinique de l'acetylcholine m4
CA3080941A1 (fr) 2017-12-22 2019-06-27 Dana-Farber Cancer Institute, Inc. Inhibiteurs de nek et procedes d'utilisation
EP3746075A4 (fr) 2018-01-29 2021-09-08 Merck Patent GmbH Inhibiteurs de gcn2 et leurs utilisations
KR20200115620A (ko) 2018-01-29 2020-10-07 메르크 파텐트 게엠베하 Gcn2 억제제 및 이의 용도
WO2019152454A1 (fr) 2018-01-30 2019-08-08 Research Development Foundation Inhibiteurs de shp2 et méthodes d'utilisation associées
CN111954668A (zh) 2018-02-08 2020-11-17 埃尼奥制药公司 稠合噻吩衍生物及其用途
SG11202006778TA (en) 2018-03-02 2020-08-28 Otsuka Pharma Co Ltd Pharmaceutical compounds
EP3768272A4 (fr) 2018-03-21 2021-08-11 Xibin Liao Inhibiteurs de jak

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107495A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Composés n-hétéroaryle substitués par un n-azaspirocycloalcane et compositions pour inhiber l'activité de shp2
WO2015107493A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine et compositions les contenant pour l'inhibition de l'activité de shp2
WO2015107494A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine et compositions les contenant pour l'inhibition de l'activité de shp2
WO2016203406A1 (fr) * 2015-06-19 2016-12-22 Novartis Ag Composés et compositions pour inhiber l'activité de shp2
WO2017216706A1 (fr) * 2016-06-14 2017-12-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité de shp2
WO2018130928A1 (fr) * 2017-01-10 2018-07-19 Novartis Ag Combinaison pharmaceutique comprenant un inhibiteur d'alk et un inhibiteur de shp2
WO2018140286A1 (fr) * 2017-01-25 2018-08-02 Indiana University Research And Technology Corporation Prophylaxie et traitement de la leucémie myéloïde aiguë
WO2018172984A1 (fr) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
"REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY", 1995, MACK PUBLISHING CO.
JORGE GARCIA FORTANET ET AL: "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 17, 12 July 2016 (2016-07-12), US, pages 7773 - 7782, XP055520685, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00680 *
KALKAVAN HALIME ET AL: "Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression", NATURE COMMUNICATIONS, NATURE PUBLISHING GROUP, UK, vol. 8, 1 March 2017 (2017-03-01), XP002782694, ISSN: 2041-1723, DOI: 10.1038/NCOMMS14447 | *
YING-NAN P. CHEN ET AL: "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases", NATURE, vol. 535, no. 7610, 29 June 2016 (2016-06-29), London, pages 148 - 152, XP055295740, ISSN: 0028-0836, DOI: 10.1038/nature18621 *

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